The lack of reliable descriptions of conformational transitions in proteins represents a critical gap in the body of structural biology knowledge. Not only are conformational transitions at the heart of many proteins' functions --- from enzymes to motor proteins --- but structural intermediates also serve as a well-established class of targets for transition-state inhibitor drugs. We therefore propose a novel computational approach to study the dramatic conformational transitions in (a) calmodulin (CAM), which mediates essential processes from gene expression to muscle contraction to mitosis, and (b) myosin, the protein motor that causes muscle contraction. The new protocol will build on extremely promising preliminary results, which demonstrate unprecedented access to physiological timescales. Combining residue-level modeling and fine-grid discretization, the approach has already proven capable of unbiased dynamic simulation of dozens of conformational transitions in each of the two 72-residue domains of calmodulin. In fact, the protocol generates several transition events per day on an inexpensive, single-processor desktop computer. This high efficiency will enable the study of myosin with modest computer resources. A multi-level approach to modeling is central to this proposal. Results generated from initial "coarse grained" models (e.g., residue-level) will be refined using a series of progressively more accurate force fields. Combined with the high-quality sampling enabled by discretization, multi-level modeling will permit a high degree of confidence in the computational data. Indeed, the simulation results --- including models of structural intermediates and the identities of kinetically critical residues --- will be used to design experiments (to be performed by collaborators) aimed toward improving our detailed understanding of structural events. Because of its speed and simplicity, the new protocol forms an ideal basis for a software tool of value to expert and non-expert alike. A detailed plan for distributing user-friendly software packages is presented, and the source code will be available for modification by expert users. [unreadable] [unreadable]